Numerous naturally occuring and semi-synthetic ergot alkaloid compounds have been shown to possess a wide variety of useful pharmacological activities. Several ergot alkaloids and their derivatives have demonstrated an ability to inhibit prolactin secretion, and consequently such compounds have shown a potential usefulness in treating prolactindependent conditions in which an undesirable excess of prolactin is present. Certain ergot compounds have thus been used in lactating rats and in rats bearing mammary tumors. Ergocornine and ergocryptine, for instance, inhibited mammary tumor growth and development in rats, as demonstrated by Cassell et al., Cancer Res., 31, 1051 (1971).
The ergot alkaloids and their derivatives are characterized as being a group of nitrogen-containing compounds having the following basic tetracyclic structure ##SPC1##
Compounds having the above general structure are referred to as ergolines. The term "ergoline" is used throughout the present specification and claims to include compounds having a 9,10-double bond, as well as the 9,10-saturated compounds exemplified by the above structure. The naturally occuring ergolines and most of the ergolines produced by partial or total synthesis are 6-methylergolines. The known ergolines differ from one another primarily in the nature of the side chain attached in the 8-position, which difference can dramatically affect the biological activity of the respective compound. For example, D-6-methyl-8-carboxy-.DELTA..sup.9 -ergoline, a 9-ergolene known by the trivial name lysergic acid, has little biological activity. In contrast, the simple diethylamide of lysergic acid is an exceptionally potent central nervous system stimulant.
Several important ergolines are characterized as being 8-methyl, 8-hydroxymethyl, and 8-(substituted)methylergolines. For example, elymoclavine is 6-methyl-8-hydroxymethyl-8-ergolene and is a potent prolactin inhibitor. D-6-methyl-8-cyanomethylergoline, prepared by Semonsky and coworkers and described in Coll. Czech. Chem. Commun., 33, 577 (1968), was found to be useful in preventing pregnancy in rats, as detailed in Nature, 221, 66 (1969), and U.S. Pat. No. 3,732,231.
To date, only one 8-alkoxymethylergoline has been prepared and isolated. In particular, Zikan and Semonsky prepared D6-methyl-8-n-butoxymethylergoline by reaction of sodium butylate and the corresponding 8-chloromethylergoline. These workers reported that the reaction, when carried out with most sodium alcoholates, led primarily to elimination of hydrochloric acid and provided the corresponding 8-methylenergoline derivative; see Coll. Czech. Chem. Comm. 39, 614 (1974). Indeed, reaction of D-6-methyl-8-chloromethylergoline with sodium methoxide under the conditions taught by Zikan and Semonsky, effected only elimination of the elements of hydrochloric acid, affording exclusively the corresponding 8-methylenergoline.
An object of this invention is to provide a process for preparing 8-alkoxymethylergolines with minimum elimination to give the 8-methylenergoline by-product. A further object of the invention is to provide hitherto unavailable 8-alkoxymethylergolines, in addition to other new ergolines.